Ultrasound irradiation inhibits proliferation of cervical cancer cells by initiating endoplasmic reticulum stress-mediated apoptosis and triggering phosphorylation of JNK.

Background: Cervical cancer is the 2nd most frequently diagnosed gynecological cancer. Therefore, it is clinically significant to discover an effective anti-cancer approach.

Objectives: This study aimed to investigate the effects of low-intensity ultrasound irradiation (USI) on cervical cancer cells and associated mechanisms of cell death.

Material And Methods: Normal human cervical HaCaT cells and cervical cancer cell lines C33A, Hela and Siha were cultured and γ-rays applied at a dosage of 2.0 Gy/min. The MTT assay was then used to assess viability (proliferation) of HaCaT, C33A, Hela, and Siha cells. Small interfering RNA (siRNA) sequences that silence the glucose-related protein (GRP78) gene were synthesized. Structural changes to cells exposed to USI were observed with scanning electron microscopy. Immunocytochemistry and western blotting were utilized to examine GRP78, C/EBP-homologous protein (CHOP), phosphorylated JNK (p-JNK), and caspase-12 expression in cervical cancer cells.

Results: Ultrasound irradiation reduced the viability of cervical cancer cells and increased apoptosis, compared to untreated tumor cells (p < 0.05). This effect was not apparent on HaCaT cells. Ultrasound irradiation also induced formation of apoptotic bodies compared to untreated tumor cells (p < 0.05), and activated endoplasmic reticulum (ER) stress-associated apoptosis compared to untreated tumor cells (p < 0.05), by triggering GRP78, CHOP and caspase-12 expression. Moreover, USI triggered ER stress by upregulating GRP78 expression. Remarkably, USI triggered phosphorylation of JNK compared to untreated tumor cells (p < 0.05). Ultrasound irradiation initiated phosphorylation of JNK by increasing GRP78 expression. Silencing of GRP78 further enhanced the effect of USI on tumor cells.

Conclusions: Ultrasound irradiation significantly inhibited proliferation and induced apoptosis of cervical cancer cells by initiating ER stress associated with apoptosis signaling pathways and triggering phosphorylation of JNK.